PROJECT SUMMARY/ABSTRACT Cancer immunotherapy attempts to boost the body's own defense mechanism ? the immune system ? to kill cancer cells and defeat cancer. Immunotherapy with T cell checkpoint inhibitors is promising to revolutionize cancer therapy. However, a major limitation of these therapies is that they are effective in only a subset of patients. Recent evidence suggests that enhanced T cell infiltration in the tumor is a predictive marker of positive response to T cell checkpoint inhibitors. Thus, failure to respond to T cell checkpoint inhibitors may correspond to a defect in the ability of the innate immune system to effectively engage adaptive anti-tumor immune response. In mice, we have identified and disabled a novel immune checkpoint mechanism, a cellular protein named MERTK, that is found in innate immune cells ? the body's first line of immune defense. MERTK limits the extent to which innate immune cells can get activated, which in turn controls how much the overall immune response would be. We have also detected the presence of MERTK in tumor-associated innate immune cells in human samples. In mouse models of cancer, genetic ablation of Mertk results in dramatic prevention of cancer growth. We propose to (i) use mouse models of cancers to investigate the mechanism/s by which loss of MERTK function improves anti-tumor immunity, (ii) test if acute ablation of Mertk in established tumors and the inactivation of its kinase activity are sufficient to overcome the failure to trigger anti- tumor T cell responses and restrict tumor growth, and (iii) to investigate the association between MERTK activation and the resistance to T cell checkpoint inhibitors in patients. Through these studies, we will better understand how the immune system can fight cancer when the MERTK brake is removed, obtain proof-of- concept for therapeutic use of drugs that would inhibit MERTK, and develop a predictive biomarker panel for the identification of a subset of patients that are likely to respond to MERTK inhibitors. In summary, our proposed studies can potentially identify a novel target for cancer immunotherapy that by itself, or in combination with FDA-approved checkpoint inhibitors or molecular targeted therapies, could significantly increase the percentage of patients that show objective response to anti-cancer therapy.